The surgical, metabolic and anatomical studies we performed during the last funding period have characterized the histopathological and mineral composition in seven groups of SF: CaOx ICSF, patients with Stones due to intestinal bypass surgery for obesity, CaP ICSF, dRTA with phosphate stones, cystine, PHT with phosphate stones, and ileostomy to test the hypothesis that interstitial plaque, arise in unique anatomical regions of the kidney, and that their formation is conditioned by specific SF pathophysiologies. We were amazed at the finding, in that, each group of SF had a unique histopathologic pattern of crystal deposition with all interstitial sites of crystalline material composed of hydroxyapatite, and intratubular sites composed of HA with a mixture of cystine, CaOx or a mixture of Na acid urate and ammonium acid urate. Aim 1 will determine mineral and ultrastructural characteristics of the plug-overgrowth-stone complex in stone formers with tuubular plugging. Aim 2 outlines a new set of studies that will determine if all kidney stones attached to sites of Randall's plaque have apatite overgrowths. These studies will advance the studies on the plaque-tissue interface already accomplished in this funding cycle. Aim 3 outlines a new series of studies to determine if normal tubules adjacent to plugged, scared tubules acquire (the field effect) cellular changes including hyaluronan expression mediated by cytokines that could lead to an acidification defect. Aim 4 will use cryo-electron microscopy with X-ray microanalysis to quantify the calcium levels in papillary tissue from CaOx ICSF patients suggesting a vas wash down mechanism for plaque formation. Aim 5a and b will determine if renal tissue protein expression of CaSR, VDR and various targets of VDR activation are increased in CaOx ICSF. Lastly, Aim 6 will determine if membrane location and/or abundance is abnormal for transporters involved in calcium handling, in those CaOx ICSF with documented markedly abnormal reduction of post-prandial calcium reabsorption compared to CaP ICSF and non-stone forming controls. These new Aims will greatly advance our understanding of the precise mechanisms of stone formation and growth, which will hopefully translate into more effective clinical treatments for stone disease.